The alternative activation of monocytes by interleukin (IL)-13 and IL-4 is a significant component of the inflammatory response. The consequences of alternative activation in inflammatory diseases remain to be determined.

In this report, we explored how integrins, receptors important for monocyte migration to inflammatory sites, regulate IL-13–mediated monocyte activation. We focused on the analysis of 2 proteins, which are upregulated during the alternative activation and are important for the development of atherosclerosis, an oxidative enzyme 15-lipoxygenase (15-LO) and a scavenger receptor CD36.

We found that adhesion of resting monocytes through β₂ integrins and inside-out activation of β₂ integrins by monocyte chemoattractant protein-1 did not change IL-13–stimulated 15-LO upregulation; however, preincubation of monocytes with the antibody MEM48, which generates full activation of β₂ integrins, significantly inhibited 15-LO mRNA and protein expression. In contrast, activation of β₁ integrins had no effect on 15-LO expression. Analysis of integrin clustering through α_M, α_L, α_X, and α_D subunits demonstrated the pivotal role for integrin α_Mβ₂ in inhibiting 15-LO expression. IL-13 treatment upregulates 15-LO–dependent CD36 expression on human monocytes; our studies showed that β₂ integrin activation and α_M integrin clustering significantly inhibited IL-13–dependent CD36 mRNA and protein expression, as well as CD36-related foam cell formation. Moreover, IL-13 stimulation of α_M-deficient peritoneal macrophages demonstrated an upregulated level of 15-LO induction, CD36 expression, and lipid accumulation as compared with wild-type controls.

The adhesion of monocytes/macrophages through activated integrin α_Mβ₂ has a regulatory and potential atheroprotective function during the alternative activation of macrophages.